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The Properties of Amyloid-β Fibrils Are Determined by their Path of Formation
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0002-9500-5917
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2018 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 13, p. 1940-1949Article in journal (Refereed) Published
Abstract [en]

Fibril formation of the amyloid-β peptide (Aβ) follows a nucleation-dependent polymerization process and is associated with Alzheimer's disease. Several different lengths of Aβ are observed in vivo, but Aβ1-40 and Aβ1-42 are the dominant forms. The fibril architectures of Aβ1-40 and Aβ1-42 differ and Aβ1-42 assemblies are generally considered more pathogenic. We show here that monomeric Aβ1-42 can be cross-templated and incorporated into the ends of Aβ1-40 fibrils, while incorporation of Aβ1-40 monomers into Aβ1-42 fibrils is very poor. We also show that via cross-templating incorporated Aβ monomers acquire the properties of the parental fibrils. The suppressed ability of Aβ1-40 to incorporate into the ends of Aβ1-42 fibrils and the capacity of Aβ1-42 monomers to adopt the properties of Aβ1-40 fibrils may thus represent two mechanisms reducing the total load of fibrils having the intrinsic, and possibly pathogenic, features of Aβ1-42 fibrils in vivo. We also show that the transfer of fibrillar properties is restricted to fibril-end templating and does not apply to cross-nucleation via the recently described path of surface-catalyzed secondary nucleation, which instead generates similar structures to those acquired via de novo primary nucleation in the absence of catalyzing seeds. Taken together these results uncover an intrinsic barrier that prevents Aβ1-40 from adopting the fibrillar properties of Aβ1-42 and exposes that the transfer of properties between amyloid-β fibrils are determined by their path of formation.

Place, publisher, year, edition, pages
Elsevier, 2018. Vol. 430, no 13, p. 1940-1949
Keywords [en]
Aβ, Cross-templating, Fibril, Surface Plasmon resonance, Thioflavin-T
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-148050DOI: 10.1016/j.jmb.2018.05.001ISI: 000436224800010PubMedID: 29751013Scopus ID: 2-s2.0-85047103029OAI: oai:DiVA.org:umu-148050DiVA, id: diva2:1218095
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2023-09-05Bibliographically approved
In thesis
1. Mechanistic and morphological studies of Aβ amyloid formation using surface plasmon resonance
Open this publication in new window or tab >>Mechanistic and morphological studies of Aβ amyloid formation using surface plasmon resonance
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Mekanistiska och morfologiska studier av Aβ amyloidbildning genom yt-plasmon resonans
Abstract [en]

Alzheimer’s disease (AD) is the most common form of dementia and apart from the individual suffering AD also causes a large economic burden for society. AD is associated with progressive neurodegeneration and atrophy of the brain. Extracellular fibrillar assemblies of the amyloid-β peptide (Aβ) in the brain represent a clinical hallmark of AD and these are today considered to be the initial cause of the disease.  The tissue-damaging properties of Aβ assemblies are, however, linked to their structures. Aβ represents a spectrum of peptides between 38-43 residues that can adopt several structures that differ both concerning their morphology and pathological properties. The mechanisms by which Aβ self-assembles, the binding strength of these structures to Aβ monomers, as well as the cross-interaction between different Aβ variants are today not fully understood. Aβ amyloid formation follows a nucleation-dependent mechanism which implies that a kinetically unfavorable nucleus must form before the formation of an amyloid fibril. The elongation of the fibril then proceeds via a template-dependent mechanism where monomeric peptides are incorporated in a highly ordered manner. Using SPR the template-dependent mode of elongation can be selectively monitored. Here, we have used the technique to probe the binding strength of Aβ fibrils and in paper 1 the role of pH and the intrinsic histidines in the Aβ sequence were investigated. The result shows that the histidines do not contribute to the previously observed increase in fibrillar strength at low pH. In paper 2 we analyzed the cross-templation between the in vivo most common variants of Aβ, represented by Aβ1-40 and Aβ1-42. Within this work, we revealed two intrinsic mechanisms preventing Aβ to adopt the structure of the significantly more pathogenic Aβ1-42 variant. In paper 3 we characterized the effect of apolipoprotein E (ApoE) on Aβ amyloid formation. ApoE is today the strongest genetic linker to the development of AD and a well-known binding partner to Aβ fibrils in vivo. Using SPR we can here show that ApoE can prevent Aβ fibril elongation. Although ApoE effectively impairs fibril formation, preventing elongation may result in alternative assemblies with higher cytotoxic properties which hence may explain its pathological effect. In paper 4 we have linked SPR to scanning electron microscopy (SEM). The work presents a novel and generic approach to simultaneously monitor the kinetic properties of amyloid formation, the binding of ligands, and its morphology. We have here specifically probed the binding properties of ApoE to Aβ fibrils, and in combination with immunogold staining technique revealed its binding pattern. Taken together this work pioneers the use of SPR as a powerful technique to elucidate Aβ amyloid formation and the complex enigma of factors causing AD. 

Place, publisher, year, edition, pages
Umeå: Umeå University, 2021. p. 57
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2155
National Category
Biochemistry and Molecular Biology Medical and Health Sciences
Research subject
medicinal chemistry; Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-188188 (URN)978-91-7855-658-8 (ISBN)978-91-7855-659-5 (ISBN)
Public defence
Glasburen, KBC, Umeå (English)
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Available from: 2021-10-08 Created: 2021-10-04 Last updated: 2021-10-05Bibliographically approved

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Brännström, KristofferIslam, TohidulGharibyan, Anna L.Iakovleva, IrinaNilsson, LinaLee, Cheng ChooSandblad, LindaPamrén, AnnelieOlofsson, Anders

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Brännström, KristofferIslam, TohidulGharibyan, Anna L.Iakovleva, IrinaNilsson, LinaLee, Cheng ChooSandblad, LindaPamrén, AnnelieOlofsson, Anders
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Department of Medical Biochemistry and Biophysics
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